Clinical applications of pharmacogenomics guided warfarin dosing

Mahajan, Pramod B.; Meyer, Kristin; Wall, Geoffrey C.; Price, Heidi J

doi:10.1007/s11096-011-9486-1

Cited by 10 publications

(8 citation statements)

References 63 publications

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“…Several studies have examined the issue of incorporating pharmacogenetic data in dosing warfarin [47,48]; however, genetic testing for warfarin dosing does not involve a change to a different medication. Several studies have also shown that genetic testing for BRCA1 / 2 leads to selection of risk-reducing surgeries [49-51], the use of post-menopausal hormone therapy [52], and pre-implantation genetic diagnosis [53].…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetic testing affects choice of therapy among women considering tamoxifen treatment

et al. 2011

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BackgroundPharmacogenetic testing holds major promise in allowing physicians to tailor therapy to patients based on genotype. However, there is little data on the impact of pharmacogenetic test results on patient and clinician choice of therapy. CYP2D6 testing among tamoxifen users offers a potential test case of the use of pharmacogenetic testing in the clinic. We evaluated the effect of CYP2D6 testing in clinical practice to determine whether genotype results affected choice of hormone therapy in a prospective cohort study.MethodsWomen planning to take or currently taking tamoxifen were considered eligible. Participants were enrolled in an informational session that reviewed the results of studies of CYP2D6 genotype on breast cancer recurrence. CYP2D6 genotyping was offered to participants using the AmpliChip CYP450 Test. Women were classified as either poor, intermediate, extensive or ultra-rapid metabolizers. Results were provided to clinicians without specific treatment recommendations. Follow-up was performed with a structured phone interview 3 to 6 months after testing to evaluate changes in medication.ResultsA total of 245 women were tested and 235 completed the follow-up survey. Six of 13 (46%) women classified as poor metabolizers reported changing treatment compared with 11 of 218 (5%) classified as intermediate, extensive or ultra-rapid metabolizers (P < 0.001). There was no difference in treatment choices between women classified as intermediate and extensive metabolizers. In multi-variate models that adjusted for age, race/ethnicity, educational status, method of referral into the study, prior knowledge of CYP2D6 testing, the patients' CYP2D6 genotype was the only significant factor that predicted a change in therapy (odds ratio 22.8; 95% confidence interval 5.2 to 98.8). Genetic testing did not affect use of co-medications that interact with CYP2D6.ConclusionsCYP2D6 genotype testing led to changes in therapy among poor metabolizers, even in the absence of definitive data that an alternative medicine improved outcomes. Pharmacogenetic testing can affect choice of therapy, even in the absence of definitive data on clinical impact.

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Section: Discussionmentioning

confidence: 99%

Pharmacogenetic testing affects choice of therapy among women considering tamoxifen treatment

et al. 2011

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“…The large interindividual variation in warfarin dose requirement is attributable to clinical, demographic, environmental factors (age, gender, body mass index, daily vitamin K intake, concomitant diseases, interaction between drugs, and smoking), and to genetic factors, which account for 40–60% of the variability [16]–[18]. Among genetic factors, single nucleotide polymorphisms (SNPs) in the CYP2C9 (Gene Bank Accession Number AY702706; chr.10q24) and in VKORC1 (Gene Bank Accession Number AY587020; chr.16p11.2) genes were first described as major contributors to dose-response variability.…”

Section: Introductionmentioning

confidence: 99%

Warfarin Anticoagulant Therapy: A Southern Italy Pharmacogenetics-Based Dosing Model

et al. 2013

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Background and AimWarfarin is the most frequently prescribed anticoagulant worldwide. However, warfarin therapy is associated with a high risk of bleeding and thromboembolic events because of a large interindividual dose-response variability. We investigated the effect of genetic and non genetic factors on warfarin dosage in a South Italian population in the attempt to setup an algorithm easily applicable in the clinical practice.Materials and MethodsA total of 266 patients from Southern Italy affected by cardiovascular diseases were enrolled and their clinical and anamnestic data recorded. All patients were genotyped for CYP2C9*2,*3, CYP4F2*3, VKORC1 -1639 G>A by the TaqMan assay and for variants VKORC1 1173 C>T and VKORC1 3730 G>A by denaturing high performance liquid chromatography and direct sequencing. The effect of genetic and not genetic factors on warfarin dose variability was tested by multiple linear regression analysis, and an algorithm based on our data was established and then validated by the Jackknife procedure.ResultsWarfarin dose variability was influenced, in decreasing order, by VKORC1-1639 G>A (29.7%), CYP2C9*3 (11.8%), age (8.5%), CYP2C9*2 (3.5%), gender (2.0%) and lastly CYP4F2*3 (1.7%); VKORC1 1173 C>T and VKORC1 3730 G>A exerted a slight effect (<1% each). Taken together, these factors accounted for 58.4% of the warfarin dose variability in our population. Data obtained with our algorithm significantly correlated with those predicted by the two online algorithms: Warfarin dosing and Pharmgkb (p<0.001; R2 = 0.805 and p<0.001; R2 = 0.773, respectively).ConclusionsOur algorithm, which is based on six polymorphisms, age and gender, is user-friendly and its application in clinical practice could improve the personalized management of patients undergoing warfarin therapy.

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“…It acts by interrupting the regeneration of dihydroxyquinone (KH2), the reduced, active form of vitamin K, by targeting vitamin K epoxide reductase complex 1 (VKORC1), leading to decreased carboxylation and activation of the vitamin K-dependent clotting factors. Warfarin use is hampered by the more than tenfold variability in dosing requirements [45,46] to achieve the target international normalized ratio (INR) in different patients. Overcoagulation causes bleeding episodes, with intracranial hemorrhage being one of the most catastrophic.…”

Section: Cyp2c9 and Vkorc1: Warfarinmentioning

confidence: 99%